Peripheral nervous system (PNS) disorders have become the foremost neurological complications among patients with HIV infection in the industrialized world. Pain, paresthesiae and gait disability characterize the clinical features arising from human immunodeficiency virus (HIV)-induced distal sensory polyneuropathy (DSP), which can be exacerbated by concurrent therapies, especially highly active antiretroviral therapy (HAART). Lentiviruses including HIV-1 and feline immunodeficiency virus (FIV) cause immunosuppression and neurological disease defined by the development of DSP. The mechanisms underlying the development of DSP remain uncertain. In particular, the initial pathogenic events leading to DSP are unknown including the primary anatomical site of injury, the temporal sequence of events and the molecular determinants underlying DSP. Our overall working hypothesis is that the early events resulting in lentivirus-induced distal sensory polyneuropathy represent convergent effects of infection/activation of macrophages and lymphocytes with ensuing pathogenic outcomes in dorsal root ganglion neurons. To test this hypothesis, we will investigate the phenotypic and mechanistic features of DSP using both ex vivo and in vivo models, including dorsal root ganglion (DRG) cultures and a feline model developed by our laboratories in which lentivirus infections cause damage to DRG sensory neurons and axons. We will define the early events leading to DSP in these models using viruses or cloned genes derived from established strains of HIV-1 and FIV, concentrating on the interactions between proteinase-activated receptor (PAR)-1 and CD154:CD40 signaling. Using an in vivo model of FIV infection, we will perform neurobehavioral analyses characterizing nociceptive and other sensory modality responses in cats together with evaluating the systemic effects of viral infection. Morphological analyses will permit characterization of different features of DSP including axonal and DRG injury. These studies will also be complemented by analyses of expression of host genes in response to infection. We will extend our studies of HIV-infected DRG cultures derived from human PNS preparations through the use of unique cell culture chambers. We will also investigate the impact of viral burden in different neural and non-neural tissues together with examining the effects of an antisense transcript encoded by FIV. In summary, we will focus on the identification of the initial site of neuronal injury and the underlying molecular mechanisms of DSP, together with assessing the contributions of specific PNS and circulating cells to the disease process. In addition, we will investigate the mechanisms by which DRG sensory neurons are injured in relation to viral replication. Relevance: Over an third of all individuals with HIV/AIDS are affected by peripheral neuropathy, which results in chronic pain, physical disability, reduced quality of life and the preclusion of the use some antiretroviral therapies. The purpose of the present proposal is to elucidate the disease-associated processes leading to peripheral neuropathy from which rational treatments can be developed. Many of the scientific techniques and models to be employed in the experiments described herein are unique to the laboratories of this team of investigators who have worked together for many years.